Endoparasiticidal compositions

ABSTRACT

The present invention relates to mixtures of avermectins, 22,23-dihydroavermectins B 1  (ivermectins) and milbemycins from the class of the macrocyclic lactones in combination with cyclic depsipeptides, optionally in the presence of praziquantel or epsiprantel, for increasing the endoparasiticidal action in endoparasiticidal compositions.

The present invention relates to mixtures of avermectins,22,23-dihydroavermectins B₁ (ivermectins) and milbemycins from the classof the macrocyclic lactones in combination with cyclic depsipeptides,optionally in the presence of praziquantel or epsiprantel, forincreasing the endoparasiticidal action in endoparasiticidalcompositions.

Gastrointestinal nematode infections of dogs are in most cases broughtabout by species of the three nemadode families Ascarididae,Ancylostomatidae and Trichuridae. In cats, it is predominantly the twonemadode families Ascarididae and Ancylostomatidae which have spreadworldwide. After passing through a number of development stages in avery great diversity of tissues of the host animals, patent infection ofthe gastrointestinal tract occurs. During the prepatency and patency ofthe infection, the parasitosis of roundworms, hookworms and whipwormscauses considerable problems, especially in young, growing dogs, catsand also in humans. Therapy or prophylactic treatment is therefore anurgent necessity in order both to cure animals already affected and tomaintain as yet uninfected animals in a healthy condition.

Consequently, the protection of dogs and cats against infection is ofvery great importance as prophylaxis against human infections,especially in children.

A series of nematicidal substances are already used as anthelminthics inanimal breeding. In order to achieve effective protection, increasinguse is being made not only of the pure compound but also of combinationsof two or more substances.

Nevertheless, the effectiveness of these known combinations againstparasites, especially at low dosages, is not always entirelysatisfactory.

In addition to the gastrointestinal helminthic diseases in dogs andcats, as already mentioned, there are further severe parasitoses, forexample filiarioses, which are highly host-specific.

The parasite Dirofilaria immitis--a filaria endemic in parts of North toSouth America, Africa, Asia and also Australia, is the cause of theimportant canine and feline cardiovascular dirofilariosis. The severepathophysiological changes within the cardiovascular system which occurduring the Dirofilaria immitis infection of dogs and cats can bringabout a dramatic course of the disease in the host animal.

Among the known compounds with anthelmintic activity, only a few possessefficiency as a prophylactic against Dirofilaria immitis.

Anthelminthics such as, for example, diethylcarbamazine (DEC), althougheffective, must be administered daily during transmission (mosquito) ofthe pathogen. With the introduction of the anthelminthicsivermectin/milbemycin from the class of the macrocyclic lactones, it hasbeen possible to reduce the prophylactic treatment of dogs and cats toone monthly administration.

Although there are endoparasiticidal agents having a high level ofefficiency against gastrointestinal nematodes and other agents with anaction against Dirofilaria immitis in dogs and cats, none of the knowncompounds has as yet shown the kind of broad-spectrum action which wouldmake it suitable for use as a therapeutic agent against allgastrointestinal nematodes and as a prophylactic agent againstDirofilaria immitis.

For this reason, a variety of active substance combinations are employedwhich exhibit an improved action and have, moreover, reducedside-effects and toxicity in the host.

In the majority of cases, the monthly prophylaxis of Dirofilaria immitisis carried out with an avermectin, for example ivermectin, from theclass of the macrocyclic lactones in combination with an anthelminthic,such as pyrantel or a benzimidazole, e.g. albendazole (cf W. C.Campbell, Ann. Rev. Microbiol. 45 (1991), pp. 445-474; J. N. Clark etal. Am. J. Vet. Res. 53(4), (1992), pp. 517-520).

A combination which may be mentioned by way of example is one consistingof 6.0 μg/kg ivermectin and 5.0 mg/kg pyrantel pamoate. While thiscombination ensures treatment and control of Ascarides (T. canis and T.leonina) and of hookworms (A. canis and U. steneocephala), it cannot beemployed against whipworms (T. vulpis). Milbemycin as well, at 500μg/kg, shows a distinct weakness in its action against the hookwormUncinaria stenocephala a gastrointestinal nematode which causes severeparasitaemia in young dogs (cf. D. D. Bowman et al. Am. J. Vet. Res. 51(1990) p. 487; R. Grieve J. Am. Vet. Assoc. 194 (1989), p. 1815).

In addition to this, ivermectin has been tested successfully in humanmedicine as an agent against filaria infections and against variousgastrointestinal nematode infections. However, these studies too haveshown that ivermectin, despite a high dosage on several days insuccession, is ineffective in hookworm and whipworm infected patients(cf Otteson & Campbell, J. Antimicrob. Chemother. 34, 1994, pp.195-203).

These reasons make it clear that avermectins, 22,23-dihydroavermectinsB₁ (ivermectins) and milbemycins from the class of the macrocycliclactones, both on their own and in combination with an anthelmintic,have not to date been able to act at the same time at low dosagesagainst roundworms, hookworms and whipworms in the gastrointestinaltract of dogs and cats.

The present invention relates to endoparasiticidal compositions whichcomprise at least one avermectin, 22,23-dihydroavermectin B₁(ivermectins) or milbemycin from the class of the macrocyclic lactonesin combination with cyclic depsipeptides consisting of amino acids andhydroxycarboxylic acids as ring structural units and 6 to 30 ring atoms,optionally in the presence of praziquantel or epsiprantel.

The compositions according to the invention, of a combination of atleast one avermectin, 22,23 dihydroavermectin B₁ (ivermectin) ormilbemycin from the class of the macrocyclic lactones with cyclicdepsipeptides consisting of amino acids and hydroxycarboxylic acids asring structural units and 6 to 30 ring atoms, exhibit an unexpectedsynergistic effect.

This synergistic effect in the endoparasiticidal composition accordingto the invention, brought about with a combination of at least oneavermectin, 22,23-dihydroavermectin B₁ (ivermectin) or milbemycin fromthe class of the macrocyclic lactones with cyclic depsipeptidesconsisting of amino acids and hydroxycarboxylic acids as ring structuralunits and 6 to 30 ring atoms, is retained even in the presence ofpraziquantel or epsiprantel.

Avermectins have been isolated as microbial metabolites from themicroorganism Streptomyces avermitilis (U.S. Pat. No. 4,310,519) and canoccur predominately as a mixture consisting of the eight componentsA_(1a), A_(1b), A_(2a), A_(2b), B_(1a), B_(1b), B_(2a) and B_(2b) (I.Putter et al. Experentia 37 (1981) p. 963, Birkhauser Verlag(Switzerland).

There is also interest in the synthetic derivatives, especially 22,23dihydroavermectin B₁ (ivermectin) (U.S. Pat. No. 4,199,569). Similarly,milbemycin B-41 D has been isolated by fermentation from Streptomyceshygroscopicus (cf. "Milbemycin: Discovery and Development" I. Junya etal. Annu. Rep. Sankyo Res. Lab. 45 (1993), pp. 1-98; JP Pat. 8 378 549;GB 1 390 336).

The use of avermectins, 22,23 dihydroavermectins B₁ (ivermectins) andmilbemycins from the class of the macrocyclic lactones asendoparasiticides has been known for a long time and is the subject ofnumerous patent applications and review articles (e.g. Biologicaleffects in: "Ivermectin and Abamectin" W. C. Campbell, Ed., SpringerVerlag, New York, N.Y., 1989; "Avermectins and Milbemycins Part II" H.G. Davies et al. Chem. Soc. Rev. 20 (1991) pp. 271-339; Chemicalmodifications in: G. Lukacs et al. (Eds.), Springer-Verlag, N.Y.,(1990), Chapter 3; Cydectin™ [moxidectin and derivatives]: G. T. Carteret al. J. Chem. Soc. Chem. Com-mun. (1987), pp. 402-404); EP 423445-A1). The use of Doramectin (Pfizer) as an endoparasiticide is alsoknown (cf. "Doramectin--a potent novel endectozide" A. C. Goudie et al.Vet. Parasitol. 49 (1993), pp. 5-15).

Furthermore, combinations of averrnectins, 22,23-dihydroavermectins B₁(ivermectins) or milbemycins with particular classes of anthelminthics,for example benzimidazoles, salicylamides, levamisole, pyrantel orpraziquantel, are the subject of numerous patent applications (e.g.: GB2 252 730; GB 2 224 933; GB 2 21 3 722; EP-A 59 074).

A cyclic depsipeptide PF 1022 A and its action against endoparasites isknown from EP-A 382 173 and EP-A 503 538 (total synthesis of PF 1022 A:JP Patent 05 229 997; Makoto Ohyama et al., Biosci. Biotech. Biochem. 58(6), 1994, pp. 1193-1194; Makio Kobayshi et al., Annu. Rep. Sankyo Res.Lab. 46, 1994, pp. 67-75; stephen J. Nelson et al., J. Antibiotics 47,(11), 1994, pp. 1322-1327).

Further cyclic depsipeptides and their endoparasiticidal action are thesubject of published or non-prior published (cyclooctadepsipeptides: WO93/19053; EP 0 634 408 A1; WO 94/19334; WO 95/07272; EP 626 375; EP 626376; cyclo-hexadepsipeptides: DE-A 4342 907; WO 93/25543; DE-A 4 437198.5; DE-A 4 440 193.0 and cyclotetradepsipeptides: EP-OS 664 297)patent applications.

Praziquantel 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]-isoquinolin-4-one and its action againstendoparasites is known from DE-P 2 362 539, U.S. Pat. No. 4,001,411.

Epsiprantel2-(cyclohexylcarbonyl)-2,3,6,7,8,12b-hexahydro-pyrazino[2,1-a][2]-benzazepin-4(1H)-oneand its action against endoparasites is known from EP-A 13 4 984, EP-A185 012.

The use of praziquantel and epsiprantel for increasing theendoparasiticidal action of cyclic depsipeptides consisting of aminoacids and hydroxycarboxylic acids as ring structural units and 6 to 30ring atoms is known from EP-A 662 326.

The present invention therefore relates to endoparasiticidalcompositions which comprise at least one avermectin,22,23-dihydroavermectin B₁ (ivermectin) or milbemycin from the class ofthe macrocyclic lactones in combination with cyclic depsipeptidesconsisting of amino acids and hydroxycarboxylic acid as ring structuralunits and 6 to 30 ring atoms, optionally in the presence of praziquantelor epsiprantel.

The present invention additionally relates to the use of avermectins,22,23di-hydroavermectins B₁ (ivermectins) and milbemycins from the classof the macrocyclic lactones in combination with cyclic depsipeptidesconsisting of amino acids and hydroxycarboxylic acids as ring structuralunits and 6 to 30 ring atoms, optionally in the presence of praziquantelor epsiprantel, for the preparation of end- parasiticidal compositions.

Examples which may be mentioned of co-components from the group of themicrobial metabolites are the avermectins and derivatives thereof. Thesecompounds constitute a mixture of macrolide lactones of the generalformula (I) ##STR1## in which the radicals R¹ to R⁴ can have the meaninggiven in Table 1 below and X can represent a single or double bondbetween the C₂₂ and C₂₃ po-sition (--C₂₂ R¹ --X--C₂₃ R² --).

In the case of a double bond there are no substituents (R¹, R²) at theC₂₂ and C₂₃ position.

                  TABLE 1                                                         ______________________________________                                        Macrocyclic lactone                                                           C.sub.22 R.sup.1 -X-C.sub.23 R.sup.2 -                                                                    R.sup.3  R.sup.4                                  ______________________________________                                        Avermectin A.sub.1a                                                                          --CH═CH--                                                  sec-Bu                               --Me                                     Avermectin A.sub.1b                                                                          --CH═CH--                                                  iso-Pr         --Me                                                           Avermectin A.sub.2a                                                                          --CH.sub.2 --CHOH--                                            sec-Bu         --Me                                                           Avermectin A.sub.2b                                                                          --CH.sub.2 --CHOH--                                            iso-Pr         --Me                                                           Avermectin B.sub.1a                                                                          --CH═CH--                                                  sec-Bu         --H                                                            Avermectin B.sub.1b                                                                          --CH═CH--                                                  iso-Pr         --H                                                            Avermectin B.sub.2a                                                                          --CH.sub.2 --CHOH--                                            sec-Bu         --H                                                            Avermectin B.sub.2b                                                                          --CH.sub.2 --CHOH--                                            iso-Pr         --H                                                            22,23-dihydroavermectin B.sub.1a                                                             --CH.sub.2 --CH.sub.2 --                                       sec-Bu         --H                                                            22,23-dihydroavermectin B.sub.1b                                                             --CH.sub.2 --CH.sub.2 --                                       iso-Pr         --H                                                            Doramectin     --CH═CH--                                                  Chx            --H                                                            ______________________________________                                    

22,23-dihydroavermectin B₁ represents ivermectin B₁ ; sec-Bu═secondarybutyl; iso--Pr═isopropyl; Chx═cyclohexyl; --Me═methyl

The avermectins and 22,23-dihydroavermectins B₁ (ivermectins) of thegeneral formula (I) are in general employed as mixtures. In thiscontext, particular interest attaches to the product abamectin, whichessentially comprises the avermectins B₁, and hydrogenation productsthereof, the 22,23-dihydroavermectins B₁ (ivermectin).

The compounds labelled "b" of the macrocyclic lactones, which possess anisopropyl radical in the C₂₅ position, need not necessarily be separatedfrom the "a" compounds, which have a sec-butyl group in the C₂₅position. Generally the mixture of both substances is isolated,consisting of>80% sec-butyl derivative (B_(1a) ) and<20% iso-propylderivative (B_(1b)), and can be used in accordance with the invention.Moreover, in the case of the stereoisomers, the substituents in the C₁₃and C₂₃ position can be arranged in both α and β configuration on thering system, i.e. can be located above or below the plane of themolecule. In each case, all of the stereoisomers are taken into accountin accordance with the invention.

The milbemycins have the same macrolide ring structure as avermectins or22,23-dihydroavermectins B₁ (ivermectins), but carry no substituent(i.e. missing oleandrose disaccharide fragment) in position 13 (R⁵═hydrogen).

As milbemycins from the class of the macrocyclic lactones, mention maybe made by way of example of the compounds having the general formula(II) ##STR2## in which the radicals R¹ to R⁵ have the meaning given inTable 2 below:

                  TABLE 2                                                         ______________________________________                                        Macrocyclic                                                                   lactone R.sup.1                                                                              R.sup.2    R.sup.3    R.sup.4                                                                            R.sup.5                             ______________________________________                                        Milbemycin                                                                            --H    --H                                                            iso-Pr                               --H  --H                                 B41 D                                                                         Nemadectin                                                                            --H    --OH                                                                                      ##STR3##  --H  --H                                 Moxidectin                                                                            --H    ═N--O--Me                                                                             ##STR4##  --H  --H                                 ______________________________________                                         iso-Pr = isopropyl                                                       

Among the co-components for the compounds of the formula (I) and (II),the following macrocyclic lactones are of particular interest inaccordance with the invention:

Avermectin B_(1a) /B_(1b)

22,23-Dihydroavermectin B_(1a) /B_(1b) (or ivermectin B_(1a) /B_(1b))

Doramectin

Moxidectin

Preferred co-components with above macrocyclic lactones of the formula(I) and (II) are, in accordance with the invention, cyclic depsipeptideshaving 24 ring atoms.

The depsipeptides with 24 ring atoms include compounds of the generalformula (III) ##STR5## in which R¹ represents optionally substitutedbenzyl, substituents which may be mentioned being hydrogen, C₁₋₄ -alkyl,especially methyl, hydroxyl, halogen, especially fluorine, C₁₋₄ -alkoxy,especially methoxy or tert-butyloxy, nitro, amino, dialkylamino,especially dimethylamino or diethylamino, N-morpholinyl, N-pyrrolidinylor N-piperidinyl,

R² represents hydrogen, C₁₋₄ -alkyl, especially methyl, hydroxyl,halogen, especially fluorine, C₁₋₄ -alkoxy, especially methoxy ortert-butyloxy, nitro, amino, dialkylamino, especially dimethylamino ordiethylamino, N-mor-pholinyl, N-pyrrolidinyl or N-piperidinyl,

where

    ______________________________________                                        a)   when R.sup.1 represents benzyl                                                R.sup.2 represents hydrogen, hydroxyl, C.sub.1-4 -alkoxy, especially          meth-                                                                         oxy, halogen, especially fluorine, alkenyloxy, especially                     allyloxy,                                                                b)   when R.sup.1 represents methyl                                                R.sup.2 represents hydrogen, hydroxyl, C.sub.1-6 -alkoxy, especially          meth-                                                                         oxy, nitro, amino, dialkylamino, especially dimethylamino,                    N-morpholinyl.                                                           ______________________________________                                    

In the context of the present invention, it is possible to use allcompounds of the general formula (III), which can exist in opticallyactive, stereoisomeric forms or as racemic mixtures. It is preferred inaccordance with the invention, however, to use the optically active,stereoisomeric forms of the compounds of the general formula (III).Particular preference is given to the use of the cyclic depsipeptidescomposed of L-configured amino acids and D-configured hydroxycarboxylicacids as ring structural units.

One example of a cyclic depsipeptide which may be mentioned is thecompound PF 1022A, known from EP-A 382 173 and EP-A 503 538, of thefollowing formula (IIIa), in which R¹ represents benzyl and R²represents hydrogen: ##STR6## Other depsipeptides which may be mentionedare the compounds known from PCT Application WO 93/19053 and EP 0 634408 A1.

Particular mention may be made of the compounds from the PCT ApplicationWO 93/19053 and EP 0 634 408 A1which are of the following formula(IIIb), in which R¹ represents (R³) substituted benzyl: ##STR7## inwhich R² and R³ represent N-morpholinyl, nitro, amino, mono- ordimethylamino.

Additional depsipeptides which may be mentioned are the compounds knownfrom PCT Application WO 94/19334.

Particular mention may be made of the compounds from PCT Application WO94/19334 which are of the following formula (IIIc), in which R¹represents benzyl: ##STR8## in which R² represents hydroxyl, methoxy ortert-butoxy.

Finally, depsipeptides which may be mentioned are the compounds knownfrom PCT Application WO 95/07272.

Particular mention may be made of the compounds from PCT Application WO95/07272 which are of the following formula (IIId), in which R¹represents methyl: ##STR9## in which R² represents methoxy,dimethylamino or N-morpholinyl.

According to the most preferred composition of the endoparasiticidalcompositions according to the invention, the 22, 23-dihydroavermectinsB_(1a) /B_(1b) (ivermectins B_(1a) /B_(1b)) of the general formula (Ia)from the class of the macrocyclic lactones ##STR10## in which R⁵represents methyl and ethyl

together with the cyclic depsipeptide PF 1022A of the formula (IIIa)##STR11## are combined with one another, optionally in the presence ofpraziquantel or epsiprantel, as co-components in the present invention,in a synergistically effective ratio.

According to a further specific preferred composition of theendoparasiticidal compositions according to the invention, the22,23-dihydroavermectins B_(1a) /B_(1b) (ivermectins B_(1a) B_(1b)) ofthe general formula (Ia) from the class of the macrocyclic lactones##STR12## in which R⁵ represents methyl and ethyl

together with the cyclic depsipeptide of the formula (IIIb) ##STR13## inwhich R² and R³ represents N-morpholinyl

are combined with one another, optionally in the presence ofpraziquantel or epsiprantel, as co-components in the present invention,in a synergistically effective ratio.

In accordance with the invention, the compounds of the forrnula (I) or(II) and (III) can also be combined with two or more of the activesubstances listed, optionally in the presence of praziquantel orepsiprantel.

The endoparasiticidal activity of the active substance combinationsaccording to the invention is markedly higher than was to be expectedfrom the actions of the individual components. Therefore, by employingthese combinations, it is possible to reduce the application rate of theindividual components. Their use, accordingly, brings with it economicand ecological advantages.

While having low toxicity to warm-blooded species, the compositionsaccording to the invention are suitable for combating pathogenicendoparasites which occur in humans and in animal keeping and animalbreeding in useful animals, breeding animals, zoo animals, laboratoryanimals, animals for experimentation and hobby animals. In this contextthey are active against all or individual stages of development of thepests and against resistant and normally sensitive species. By combatingthe pathogenic endoparasites the intention is to reduce disease,mortality and reductions in yield (for example in the production ofmeat, milk, wool, hides, eggs, honey, etc.), so that the use of theactive substances enables more economic and simpler animal keeping. Thepathogenic endoparasites include cestodes, trematodes, nematodes andAcantocephala, in particular:

From the order of the Pseudophyllidea, for example: Diphyllobothriumspp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridiumspp., Diplogonoporus spp.

From the order of the Cyclophyllidea, for example: Mesocestoides spp.,Anoplocephala spp., Paranoplocephala spp., Moniezia spp., ThysanosomsaSpp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaeniaspp., Andyra spp.,

Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp.,Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp.,Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp.,Diplopylidium spp.

From the subclass of the Monogenea, for example: Gyrodactylus spp.,Dactylogyrus spp., Polystoma spp.

From the subclass of the Digenea, for example: Diplostomum spp.,Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp.,Omithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp.,Leucochloridium spp., Brachylaima spp., Echinostoma spp.,Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciolaspp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp.,Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoronspp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp.,Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimusspp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimusspp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchisspp. Metorchis spp., Heterophyes spp., Metagonimus spp.

From the order of the Enoplida, for example: Trichuris spp., Capillariaspp., Trichomosoides spp., Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp.,Strongyloides spp

From the order of the Strongylida, for example: Strongylus spp.,Triodontophorus spp., Oesophagodontus spp., Trichonema spp.,Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp.,Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp.,Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,Bunostomum spp.,

Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylusspp., Dictyocaulus spp., Muellerius spp., protostrongylus spp.,Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulusspp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp.,Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp.,Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchusspp., Ostertagia spp., Marshallagia spp., Cooperia spp.,

Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomumspp., Ollulanus spp.

From the order of the Oxyurida, for example: Oxyuris spp., Enterobiusspp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of the Ascaridia, for example: Ascaris spp., Toxascarisspp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of the Spirurida, for example: Gnathostoma spp.,Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp.,Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida, for example: Stephanofilaria spp.,Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoidesspp., Brugia spp., Wuchereria spp., Onchocerca spp.

From the order of the Gigantorhynchida, for example: Filicollis spp.,Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

The useful and breeding animals include mammals, such as, for example,cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys,rabbits, fallow deer, reindeer, fur-bearing animals, such as, forexample, mink, chinchilla or racoon, birds, such as, for example,chickens, geese, turkeys, ducks or ostriches, freshwater fish and seafish, such as, for example, trout, carp and eels, reptiles and insects,such as, for example, honeybee and silkworm.

The laboratory and experimentation animals include mice, rats, guineapigs, golden hamsters, dogs and cats.

The hobby animals include dogs and cats.

Administration can be effected prophylactically as well astherapeutically.

The active substances are administered, either directly or in the formof suitable preparations, enterally, parenterally, dermally, nasally, bytreating the environment or with the aid of shaped articles containingthe active substance, such as, for example, strips, plates, tapes, neckbands, ear tags, limb bands or marking devices.

Enteral administration of the active substances is effected, forexample, orally in the form of powders, tablets, capsules, pastes,drinks, granules, solutions which can be applied orally, suspensions andemulsions, boli, medicated feed or drinking water. Dermal application iseffected, for example, in the form of dipping, spraying, or pouring-onand spotting-on. Parenteral administration is effected, for example, inthe form of injection (intramuscular, subcutaneous, intravenous orintraperitoneal) or by implants.

The following are suitable preparations:

solutions, such as solutions for injection, oral solutions, concentratesfor oral administration after dilution, solutions for use on the skin orin body cavities, pour-on formulations, gels;

emulsions and suspension for oral or dermal administration and forinjection; semi-solid preparations;

formulations in which the active substance is incorporated in a creambase or in an oil-in-water or water-in-oil emulsion base;

solid preparations, such as powders, premixes or concentrates, granules,pellets, tablets, boli, capsules; aerosols and inhalants, shapedarticles containing the active substance.

Solutions for injection are administered intravenously, intramuscularlyand subcutaneously.

Solutions for injection are prepared by dissolving the active substancein a suitable solvent and, if desired, adding additives, such assolubilizers, acids, bases, buffer salts, antioxidants, orpreservatives. The solutions are sterile-filtered and dispensed intocontainers.

The following may be mentioned as solvents: physiologically acceptablesolvents, such as water, alcohols, such as ethanol, butanol, benzylalcohol, glycerol, propylene glycol, polyethylene glycols andN-methyl-pyrrolidone, and their mixtures.

If appropriate, the active substances can also be dissolved inphysiologically acceptable vegetable or synthetic oils which aresuitable for injection.

The following may be mentioned as solubilizers: solvents whichfacilitate the dissolution of the active substance in the main solventor which prevent precipitation of the active substance. Examples ofsolubilizers are polyvinylpyrrolidone, polyoxyethylated castor oil andpolyoxyethylated sorbitan esters.

The following are preservatives: benzyl alcohol, trichlorobutanol,p-hydroxy-benzoic esters or n-butanol.

Oral solutions are administered directly. Concentrates are first dilutedto the administration concentration and then administered orally. Oralsolutions and concentrates are prepared as described above in the caseof the solutions for injection, sterile procedures not being necessary.

Solutions for use on the skin are applied drop by drop, smoothed on,rubbed in, splashed on or sprayed on. These solutions are prepared asdescribed above in the case of the solutions for injection.

It may be advantageous to add thickeners in the preparation process. Thefollowing are thickeners: inorganic thickeners, such as bentonites,colloidal silica, aluminium monostearate, or organic thickeners, such ascellulose derivatives, polyvinyl alcohols and their copolymers,acrylates and metacrylates.

Gels are applied to the skin or smoothed on or introduced into bodycavities. Gels are prepared by adding such an amount of thickener tosolutions which have been prepared as described in the case of thesolutions for injection that a clear composition is formed which has anointment-like consistency. The thickeners used are the thickenersindicated further above.

Pour-on and spot-on formulations are poured or splashed onto limitedareas of the skin, the active substance penetrating the skin and actingsystemically.

Pour-on and spot-on formulations are prepared by dissolving, suspendingor emulsifying the active substance in suitable solvents or solventmixtures which are tolerated by the skin. If appropriate, otherauxiliaries, such as colourants, absorption accelerators, antioxidants,light stabilizers or tackifiers, are added.

The following may be mentioned as solvents: water, alkanols, glycols,polyethylene glycols, polypropylene glycols, glycerol, aromaticalcohols, such as benzyl alcohol, phenylethanol or phenoxyethanol,esters, such as ethyl acetate, butyl acetate or benzyl benzoate, ethers,such as alkylene glycol alkyl ethers, such as dipropylene glycolmonomethyl ether or diethylene glycol mono-butyl ether, ketones, such asacetone or methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons,vegetable or synthetic oils, DMF, dimethylacetamide,N-methyl-pyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3 -dioxolane.

Colourants are all colourants which can be dissolved or suspended andwhich are approved for use in animals.

Examples of absorption accelerators are DMSO, spreading oils, such asisopropyl myristate, dipropylene glycol pelargonate, silicone oils,fatty acid esters, triglycerides or fatty alcohols.

The following are antioxidants: sulphites or metabisulphites, such aspotassium metabisulphite, ascorbic acid, butylhydroxytoluene,butylhydroxyanisole or tocopherol.

Examples of light stabilizers are novantisolic acid.

Tackifiers are, for example, cellulose derivatives, starch derivatives,polyacrylates or natural polymers such as alginates or gelatin.

Emulsions can be administered orally, dermally or as injections.

Emulsions are either the water-in-oil type or the oil-in-water type.

They are prepared by dissolving the active compound either in thehydrophobic or in the hydrophilic phase and by homogenizing this phasewith the solvent of the other phase, with the aid of suitableemulsifiers and, if appropriate, other auxiliaries, such as colourants,resorption accelerators, preservatives, antioxidants, light stabilizers,and viscosity-increasing substances.

The following may be mentioned as the hydrophobic phase (oils): paraffinoils, silicone oils, natural vegetable oils, such as sesame seed oil,almond oil or castor oil, synthetic triglycerides, such ascaprylic/capric acid biglyceride, a triglyceride mixture with vegetablefatty acids of chain length C₈₋₁₂ or other specifically selected naturalfatty acids, mixtures of partial glycerides of saturated or unsaturatedfatty acids which may also contain hydroxyl groups, and mono- anddiglycerides of the C₈ /C₁₀ -fatty acids.

Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyllaurate, dipropylene glycol pelargonate, esters of a branched fatty acidhaving a medium chain length with saturated fatty alcohols of chainlength C₁₆ -C₁₈, isopropyl myristate, isopropyl palmitate,caprylic/capric esters of saturated fatty alcohols of chain length C₁₂-C₁₈, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate,ethyl lactate, waxy fatty acid esters, such as artificial duck uropygialfat, dibutyl phthalate, diisopropyl adipate, ester mixtures related tothe latter, etc.

Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol,cetylstearyl alcohol or oleyl alcohol.

Fatty acids, such as, for example, oleic acid and its mixtures.

The following may be mentioned as the hydrophilic phase: water,alcohols, such as, for example, propylene glycol, glycerol, sorbitol andtheir mixtures.

The following may be mentioned as emulsifiers: non-ionic surfactants,for example polyoxyethylated castor oil, polyoxyethylated sorbitanmonooleate, sorbitan monostearate, glycerol monostearate, polyoxyethylstearate or alkylphenol polyglycol ethers;

ampholytic surfactants, such as disodium N-lauryl-β-iminodipropionate orlecithin;

anionic surfactants, such as Na lauryl sulphate, fatty alcohol ethersulphates, and the monoethanolamine salt of mono/dialkylpolyglycol etherorthophosphoric ester;

cationic surfactants, such as cetyltrimethylammonium chloride.

The following may be mentioned as other auxiliaries: substances whichincrease the viscosity and stabilize the emulsion, such ascarboxymethylcellulose, methylcellulose and other cellulose and starchderivatives, polyacrylates, alginates, gelatin, gum arabic,polyvinylpyrrolidone, polyvinylalcohol, methylvinyl ether/maleicanhydride copolymers, polyethylene glycols, waxes, colloidal silica, ormixtures of the listed substances.

Suspensions can be administered orally, dermally or as an injection.They are prepared by suspending the active substance in a liquidexcipient, if appropriate with the addition of other auxiliaries, suchas wetting agents, colourants, resorption accelerators, preservatives,antioxidants and light stabilizers.

Liquid excipients which may be mentioned are all homogeneous solventsand solvent mixtures.

Wetting agents (dispersants) which may be mentioned are the surfactantsindicated further above.

Other auxiliaries which may be mentioned are those indicated furtherabove.

Semi-solid preparations can be administered orally or dermally. They areonly distinguished from the above-described suspensions and emulsions bytheir higher viscosity.

To prepare solid preparations, the active substance is mixed withsuitable excipients, if appropriate with the addition of auxiliaries,and the mixture is formulated as desired.

Excipients which may be mentioned are all physiologically acceptablesolid inert substances. Suitable for this purpose are inorganic andorganic substances. Inorganic substances are, for example, common salt,carbonates, such as calcium carbonate, hydrogen carbonates, aluminiumoxides, silicas, clays, precipitated or colloidal silicon dioxide, andphosphates.

Organic substances are, for example, sugars, cellulose, foodstuffs andanimal feeds, such as powdered milk, animal meals, cereal meals, coarsecereal meals and starches.

Auxiliaries are preservatives, antioxidants and colourants which havealready been mentioned further above.

Other suitable auxiliaries are lubricants and glidants, such as, forexample, magnesium stearate, stearic acid, talc, bentonites,disintegrants, such as starch or crosslinked polyvinylpyrrolidone,binders, such as, for example, starch, gelatin or linearpolyvinylpyrrolidone, and dry binders, such as microcrystallinecellulose.

In the preparations, the active substances can also be present inmixtures with synergists or other active compounds which are activeagainst pathogenic endoparasites. Examples of such active compounds areL-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazole carbamates,pyrantel.

Ready-to-use preparations contain the active substances inconcentrations of 10 ppm to 20 per cent by weight, preferably from 0.1to 10 per cent by weight.

Preparations which are diluted before use contain the active substancesin concentrations of 0.5 to 90% by weight, preferably from 5 to 50 percent by weight.

In the endoparasiticidal compositions according to the invention, wherethey are employed in the dog as a hobby animal, in general a weightratio of macrocyclic lactone to depsipeptide of 1:500 to 1000,preferably 1:500 to 850, very particularly preferably 1:500, isobserved.

Furthermore, in the endoparasiticidal compositions according to theinvention, where they are employed in the cat as a hobby animal, ingeneral a weight ratio of macrocyclic lactone to depsipeptide of 1:150to 500, preferably 1:150 to 350, very particularly preferably 1:150 to200, is observed.

Finally, in the endoparasiticidal compositions according to theinvention, where they are employed in useful animals, in general aweight ratio of macrocyclic

lactone to depsipeptide of 1:20 to 400, preferably 1:20 to 250, veryparticularly preferably 1:20 to 50, is observed.

In the context of the present invention, the endoparasiticidalcompositions can comprise not only at least one macrocyclic lactone anddepsipeptides but also praziquantel or epsiprantel. In these cases, theweight ratio of macrocyclic lactone to praziquantel or epsiprantelgenerally used in the combination according to the invention is thatwhich corresponds to the weight ratio of the depsipeptide.

EXPERIMENTAL SECTION EXAMPLE A

In vivo nematode test

Nematospiroides dubius in the Mouse

Mice are infected experimentally with nematodes of the speciesNematospiroides dubius. For infection, the mice are administered orallywith Nematospiroides dubius as 60 filariform larvae.

After the prepatency period has expired, the suspended active substancesare administered orally on day 12 after infection.

Determination of the Activity

The mice are selected on day 20 after infection. The adult parasites inthe Duodenum are counted by means of a compressor. The success oftreatment in the dose group is made relative to the untreated controlgroup.

Tables A and B below indicate the action of the combination againstNematospiroides dubius in the mouse.

                  TABLE A                                                         ______________________________________                                        Action of the combination of PF 1022 A and ivermectin B.sub.1a /B.sub.1b      against Nematospiroides dubius in the mouse after oral                        administration                                                                                      Reduction rate                                          Active substance and amount [mg/kg]                                                                 [%]                                                     ______________________________________                                        PF 1022 A         50.0    0                                                   Ivermectin B.sub.1a /B.sub.1b                                                                   0.1     0                                                   PF1022 A          50.0    100                                                 + Ivermectin B.sub.1a /B.sub.1b                                                                 0.1                                                         PF 1022 A         25.0    0                                                   PF1022 A          25.0    >80                                                 + Ivermectin B.sub.1a /B.sub.1b                                                                 0.1                                                         ______________________________________                                    

                  TABLE B                                                         ______________________________________                                        Action of the combination of PF 1022 A and ivermectin B.sub.1a /B.sub.1b      in                                                                            the presence of praziquantel against Nematospiroides dubius in the            mouse after oral administration                                               Active substance and amount [mg/kg]                                                                Reduction rate [%]                                       ______________________________________                                        PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   10.0                                                         PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   5.0                                                          PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   1.0                                                          PF1022 A         25.0    >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   10.0                                                         PF1022 A         25.0    >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   5.0                                                          PF1022 A         25.0    >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   1.0                                                          ______________________________________                                    

EXAMPLE B

In vivo nematode test

Heterakis spumosa in the Mouse

Mice are infected experimentally with nematodes of the species Heterakisspumosa. For infection, the mice are administered orally with Heterakisspumosa as 90 embryonate eggs.

After the prepatency period has expired, the suspended active substancesare administered orally on day 46 after infection.

Determination of the Activity

The mice are selected on day 54 after infection. The adult parasites arecounted in the colon and caecum using a microscope. The success oftreatment in the dose group is made relative to the untreated controlgroup.

Tables C and D below indicate the action of the combination againstHeterakis spumosa in the mouse.

                  TABLE C                                                         ______________________________________                                        Action of the combination of PF 1022 A and ivermectin B.sub.1a /B.sub.1b      against Heterakis spumosa in the mouse after oral administration              Active substance and amount [mg/kg]                                                                Reduction rate [%]                                       ______________________________________                                        PF 1022 A        50.0    0                                                    Ivermectin B.sub.1a /B.sub.1b                                                                  0.1     <50                                                  PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          PF 1022 A        25.0    0                                                    PF1022 A         25.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          PF 1022 A        10.0    0                                                    PF1022 A         10.0    >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          PF 1022 A        5.0     0                                                    PF1022 A         5.0     >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          ______________________________________                                    

                  TABLE D                                                         ______________________________________                                        Action of the combination of PF 1022 A and ivermectin B.sub.1a /B.sub.1b      in                                                                            the presence of praziquantel against Heterakis spumosa in the                 mouse after oral administration                                               Active substance and amount [mg/kg]                                                                Reduction rate [%]                                       ______________________________________                                        PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   10.0                                                         PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   5.0                                                          PF1022 A         50.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   1.0                                                          PF1022 A         25.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   10.0                                                         PF1022 A         25.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   5.0                                                          PF1022 A         25.0    100                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0.1                                                          + Praziquantel   1.0                                                          ______________________________________                                    

EXAMPLE C

In-vivo nematode test

Ancylostoma caninum in dogs

Beagle puppies were experimentally infested with hookworms (Ancylostomacaninum). Amount of infestation material were 250 L₃ larvae.

After the prepatent period, when mature worms are present within thegastrointestinal tract, the dogs were orally treated with the testcompounds as pure active in gelatine capsules.

Determination of the Efficacy was Carried Out According to the FollowingTwo Methods

1. Counts of worm eggs within the dogs faces before and after treatment.

2. Percent efficacy at a critical test calculated using the formula:##EQU1##

Table E shows the action of the combination against Ancylostoma caninumin dogs.

                  TABLE E                                                         ______________________________________                                        Action of the combination of PF 1022 A and Ivermectin B.sub.1a /B.sub.1b      against Ancylostoma caninum in dogs after oral application                    Active substance and amount [mg/kg]                                                                Reduction rate [%]                                       ______________________________________                                        PF 1022 A        1,0     100                                                                   0,5     0                                                    Ivermectin B.sub.1a /B.sub.1b                                                                  0,01    100                                                                   0,001   0                                                    PF 1022 A        0,5     >80                                                  + Ivermectin B.sub.1a /B.sub.1b                                                                0,001                                                        ______________________________________                                    

What is claimed is:
 1. Synergistic endoparasiticidal compositions whichcomprise at least one avermectin, 22,23-dihydroavermectin B₁(ivermectins) or milbemycin from the class of the macrocyclic lactonesin combonation with cyclic depsipeptides consisting of amino acids andhydroxycarboxylic acids as ring structural units and 6 to 30 ring atoms,optionally in the presence of praziquantel or epsiprantel. 2.Endoparasiticidal compositions according to claim 1 for dogs, whereinthe weight ratio of macrocyclic lactone to depsipeptide is 1:500 to1000.
 3. Endoparasiticidal compositions according to claim 2, whereinsaid ratio is 1:500 to
 850. 4. Endoparasiticidal compositions accordingto claim 3, wherein said ratio is 1:500.
 5. Endoparasiticidalcompositions according to claim 1 for cats, wherein the weight ratio ofmacrocyclic lactone to depsipeptide is 1:150 to
 500. 6.Endoparasiticidal compositions according to claim 5, wherein said ratiois 1:150 to
 350. 7. Endoparasiticidal compositions according to claim 6,wherein said ratio is 1:150 to
 200. 8. Endoparasiticidal compositionsaccording to claim 1 for cattle, horses, sheep, pigs, goats, camels,water buffaloes, donkeys, rabbits, fallow deer, reindeer, mink,chinchilla, raccoon, birds, fish, reptiles and insects, wherein theweight ratio of macrocyclic lactone to depsipeptide is 1:20 to
 4000. 9.Endoparasiticidal compositions according to claim 8, wherein said ratiois 1:20 to
 250. 10. Endoparasiticidal compositions according to claim 9,wherein said ratio is 1:20 to
 50. 11. Endoparasiticidal compositionsaccording to any one of claim 1 characterized in that the ivermectinsare selected from the B₁ series B_(1a) and B_(1b).
 12. Endoparasiticidalcompositions according to any one of claim 1 characterized in that theavermectins are selected from the B₁ series B_(1a) and B_(1b). 13.Endoparasiticidal compositions according to any one of claim 1characterized in that the macrocyclic lactones are selected fromdoramectin and moxidectin.
 14. Endoparasiticidal compositions accordingto any one of claim 1 characterized in that the cyclic depsipeptides areof the formula (III): ##STR14## in which R₁ represents benzyl optionallysubstituted by hydrogen, C₁₋₄ -alkyl, hydroxyl, halogen, C₁₋₄ -alkoxy,nitro, amino, dialkylamino, N-morpholinyl, N-pyrrolidinyl orN-piperidinyl,R₂ represents hydrogen, C₁₋₄ -alkyl, hydroxyl, halogen,C₁₋₄ -alkoxy, nitro, amino, dialkylamino, N-morpholinyl, N-pyrrolidinylor N-piperidinyl, wherea) when R₁ represents benzylR₂ representshydrogen, hydroxyl, C₁₋₄ -alkoxy, halogen or alkenyloxy, b) when R₁represents methylR₂ represents hydrogen, hydroxyl, C₁₋₆ -alkoxy, nitro,amino, dialkylamino, or N-morpholinyl.
 15. Endoparasiticidalcompositions according to any one of claim 1 characterized in that thecyclic depsipeptide is of the formula (IIIa): ##STR15## 16.Endoparasiticidal compositions according to any one of claim 1characaterized in that the cyclic depsipeptide is of the formula (IIIb):in whichR₂ and R₃ represent N-morpholinyl, nitro, amino, mono- ordimethylamino.
 17. Endoparasiticidal compositions according to any oneof claim 1 characterized in that the cyclic depsipeptide is of theformula (IIIc): ##STR16## in which R₂ represents hydroxyl, methoxy ortert-butoxy.
 18. Endoparasiticidal compositions according to any one ofclaim 1 characterized in that the cyclic depsipeptide is of the formula(IIId): ##STR17## in which R₂ represents methoxy, dimethylamino orN-morpholinyl.
 19. Endoparasiticidal compositions according to any oneof claim 1 comprising a compound of the general formula (Ia): ##STR18##in which R₅ represents methyl and ethyl together with the cyclicdepsipeptide PF 1022A of the formula (IIIa) ##STR19## and optionallypraziquantel or epsiprantel.
 20. Endoparasiticidal compositionsaccording to any one of claim 1 comprising a compound of the generalformula (Ia): ##STR20## in which R₅ represents methyl and ethyl togetherwith the cyclic depsipeptide of the formula (IIIb) ##STR21## in which R₂and R₃ represent N-morpholinyl and optionally praziquantel orepsiprantel.